SUMMARY Alzheimers disease (AD), the leading cause of dementia in the elderly, is a devastating disease for which treatment in later stages is currently not possible. In order to be able to develop and apply treatments in earlier stages of the disease, there is a need for biomarkers that can show the initiation of the disease process, even while clinical symptoms are not yet present, which would allow one to stop or delay the disease progression before irreversible damage has been done. For this supplement to our parent biomedical technology resource Center (BTRC) P41 grant, we propose to acquire pilot data for developing a biomarker multi-atlas for AD. A multi-atlas takes into account the changes in brain shapes to be able to better separate age-dependent from disease dependent changes in biomarker images. This study will involve the acquisition of data for 25 MCI patients and 25 age-matched healthy controls (ages 60-85) with three novel types of physiological contrast in addition to standard anatomical measures. The three physiological measures are (i) imaging of mobile and immobile protein content in brain tissue using so-called amide proton transfer weighted (APTw) MRI and magnetization transfer contrast (MTC) MRI, respectively. AD is associated with accumulations of abnormal proteins (amyloid plaques, neurofibrillary tangles) in the central nervous system. We hypothesize that the accumulations of abnormal cytoplasmic proteins may be associated with high APT signal early on and increased MTC signal later on; (ii) imaging of the average magnetic susceptibility of tissue using quantitative susceptibility mapping (QSM). Magnetic susceptibility is the physical quantity that describes the degree of magnetization of a material in response to an applied magnetic field, which has been shown to be proportional to iron content in gray matter. Iron accumulation was previously observed in brain regions characterized by Ab deposition and in neurons with intraneuronal neurofibrillary tangles in AD. We hypothesize that QSM mapping may be able to detect early changing in iron content before irreversible disease processes take place. (iii) measurement of cerebrovascular reactivity (CVR), an early indicator of vascular compliance, a parameter more and more considered to be of great relevance in early development of dementia and for separation of the development of vascular dementia from the development of AD. The brain?s ability during performance of a cognitive task is a dynamic process and requires small blood vessels to dilate or constrict in real time to adjust blood flow in a region-specific manner. We hypothesize that measurement of CVR can detect early changes in small vessel function in the aging brain and also be used to differentiate vascular cognitive impairment from AD dementia. While this limited set will not allow conclusive results with respect to MCI and AD, this pilot study will allow us to get a first preliminary data set to judge the feasibility of a larger study for which we would request funding through the RO1 mechanism using the established data.